KR840009108A - Process for preparing amino-lower alkyl fenbene compound - Google Patents

Abstract

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Description

Process for preparing amino-lower alkyl fenbene compound

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Claims (15)

The lylide compound of the general formula (II) is closed or the compound of the general formula (III) is treated with an organic compound of trivalent phosphorus, and optionally, the radical R ₁ in the compound of the general formula (I) Converts the protected hydroxy group to a free hydroxy group, and / or optionally protects the protected carboxyl group R ₂ ′ from the free compound or of the different protected carboxyl group R ₂ ′ in the compound of formula (I). Or convert free carboxyl group R ₂ to protected carboxyl group R ₂ ′ and / or optionally convert protected amino group R ₃ to free amino group or free amino group R ₃ to substituted amino And / or convert the resulting compounds having salt forming groups into salts, convert the resulting salts into free compounds or different salts, and / or optionally Compounds of general formula (I), salts of compounds of general formula (I) containing salt-forming groups, characterized in that the mixture of the isomeric compounds of general formula (I) Optical isomers of the compounds of I) and methods of preparing mixtures of such optical isomers. Wherein R ₁ represents lower alkyl substituted by hydroxy or protected hydroxy, R ₂ represents carboxy or protected carboxy R ₂ ′, R ₃ is amino, lower alkyl substituted amino, substituted methylene Amino or protected amino, and A represents straight chain lower alkylene substituted with lower alkyl, provided that when A is lower alkylene which is linear substituted with two methyl groups, R ₁ is 1-hydroxyethyl Or is not protected 1-hydroxy ethyl, R ₂ is as defined above, R ₃ represents amino or protected amino), Z represents oxygen or sulfur, and X ⁺ is 3-substituted containing cation Phosphonio groups or 2-esterified phosphono groups. The compound of claim 1, wherein R ₁ represents lower alkyl substituted with hydroxy or protected hydroxy, R ₂ represents carboxy or protected carboxy, R ₃ represents amino, lower alkyl amino, di-lower alkylamino, Group of the formula-N = C (X ₁ , X ₂ ), wherein X ₁ is hydrogen, amino, lower alkylamino, di-lower amino, lower alkyleneamino, nitroamino, hydrazino, anilino, lower Alkoxy, phenyl-lower alkoxy, lower alkylthio, lower alkyl, amino-lower alkyl, N-lower alkylamino-lower alkyl, N, N-di-lower alkylamino, -lower alkyl, lower alkenyl, phenyl, pyridyl , For example 2- or 4-pyridyl, thienyl, for example 2-thienyl, or thiazolyl, for example 4-thiazolyl, X ₂ represents amino loweralkylamino, di-lower-alkylamino , Lower alkylene amino, hydrazino, anilino, lower alkoxy, phenyl-lower alkoxy or lower alkyl Thio, R ₃ is protected amino, and A represents straight chain lower alkylene substituted with lower alkyl having 1 to 4 carbon atoms, provided that R _{1 is} a straight chain lower alkylene substituted with two methyl groups. Is not 1-hydroxyethyl or protected 1-hydroxyethyl, R _{2 is} as defined above, and R ₃ is a compound of formula (I) which represents amino or protected amino, having a salting group A process for preparing a mixture of optical isomers and optical isomers of a compound of general formula (I) having a chital center in the salt of the compound of (I), radicals R ₁ and / or A. The compound of claim 1, wherein R ₁ is hydroxy. Lower alkyl substituted with tri-lower alkylsilyloxy, 2-halo-lower alkoxy, 2-halo-lower alkoxy-carbonyloxy or optionally nitro-substituted phenyl lower alkoxycarbonyloxy, R ₂ is carboxy, lower Alkenyloxycarbonyl, optionally nitro-substituted benzyloxycarbonyl, lower alkanoylmethoxycarbonyl, 2-halo lower alkoxycarbonyl, 2-tri-lower alkylsilyl ethoxycarbonyl or degradable under physiological conditions Esterified carboxy groups such as 1-lower alkoxy carbonyloxy-lower alkoxycarbonyl, lower alkanoyloxy methoxycarbonyl -Amino-lower alkanoyloxymethoxy carbonyl or phthalidyloxycarbonyl and R ₃ is amino, lower alkylamino, di-lower alkylamino, a group of formula -N = C (X ₁ , X ₂ ) , Wherein X ₁ represents hydrogen, amino, lower alkylamino lower alkyl, phenyl or pyridyl, for example 2-pyridyl, X ₂ represents hydrogen, amino, lower alkylamino or dilower alkylamino, or R ₃ is azido, phthalimino, nitro, lower alkenyloxycarbonylamino, optionally nitro-substituted benzyloxy carbonylamino, 1-lower alkanoyl-lower alk-1-en-2-ylamino or 1 Lower alkoxycarbonyl-lower alk-1-en-2-yl amino and A represents a straight chain lower alkylene mono- or di-substituted with lower alkyl having 1 to 4 carbon atoms, provided that A is two methyl R ₁ represents 1-hydroxyethyl or protected 1 A salt of a compound of formula (I) having a salting group and a salt of a compound of formula (I), which is not hydroxy ethyl, R ₂ is as defined above, and R ₃ is amino or protected amino, And / or an optical isomer of a compound of general formula (I) having a chiral center in A, and a process for preparing a mixture of these optical isomers. 2. A compound according to claim 1, wherein R ₁ represents lower alkyl substituted with hydroxy, A represents C1-C4, mono-substituted lower alkylene mono-substituted with methyl or ethyl, or R ₁ represents hydroxymethyl And A represents 1 to 4 carbon atoms and represents a straight chain lower alkylene 2-substituted with methyl or ethyl, in which case R ₂ is carboxy, 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl or lower alkanoyloxy Chiral in the salts, radicals R ₁ and or A of compounds of formula (I) and compounds of formula (I), which represents methoxy carbonyl and in each case R ₃ represents amino, lower alkylamino or formamidino A method for producing optical isomers of compounds of general formula (I) having a center and mixtures of these optical isomers. The compound of claim 1, wherein R ₁ represents hydroxymethyl or 1-hydroxyethyl, A represents ethylene or 1,3-propylene mono-substituted with methyl or ethyl, respectively, and R ₁ represents hydroxymethyl To prepare a salt of a compound of formula (I) and a compound of formula (I) wherein A represents ethylene disubstituted with methyl, in each case R ₂ represents carboxy, and in each case R ₃ represents amino Way. A compound of formula (I) having a chiral center on substituents R ₁ and / or A, in particular (1'R) of a compound of formula (I) wherein R ₁ represents 1'-hydroxyethyl Process for preparing salts of isomers- and compounds of general formula (I). A process according to claim 1 for preparing a pharmaceutically toxic salt of the compound of formula (I). The process according to claim 1, wherein an ester of a compound of formula (I) is degradable in a physiological state. The compound of claim 1, wherein (5R, 6S) -2 [(2R, S) -2-aminoprop-1-yl] -6-hydroxymethyl-2-phenem-3-carboxylic acid and pharmaceutically nontoxic How to prepare a salt. The compound according to claim 1, wherein (5R, 6S) -2- (2-amino-2-methylprop-1-yl) -6-hydroxy methyl-2-phenem-3-carboxylic acid and its pharmaceutically nontoxic How to prepare a salt. The compound of claim 1, wherein (5R, 6S) -2 [(3R, S) -3-aminobut-1-yl] -6-hydroxymethyl-2-phenem-3-carboxylic acid and its pharmaceutically nontoxic How to prepare a salt. The process of claim 1, wherein (5R, 6S) -2- (1-formamidinoethyl) -6-hydroxymethyl-2-phenem-3-carboxylic acid and pharmaceutically nontoxic salts thereof are prepared. A process according to claim 1 for preparing (5R, 6S) -2 [(1S) -1-aminoethyl-1] -6-hydroxymethyl-2-phenem-3-carboxylic acid and pharmaceutically nontoxic salts thereof. Way. A process according to claim 1 for preparing (5R, 6S) -2 [(1S) -1-aminoethyl-1] -6-hydroxymethyl-2-phenem-3-carboxylic acid and pharmaceutically nontoxic salts thereof. Way. The compound of claim 1, wherein (5R, 6S) -2-[(2R, S-2-aminobut-1-yl] -6-hydroxymethyl-2-phenem-3-carboxylic acid and its pharmaceutically nontoxic How to prepare a salt. ※ Note: The disclosure is based on the initial application.